A Phase I–II trial of polyethylene glycol‐conjugated L‐asparaginase in patients with multiple myeloma

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Abstract
BACKGROUND Multiple myeloma remains an incurable disease. New agents are needed to improve therapy for patients with this disease. Previous investigators evaluated in vitro sensitivity of myeloma cells to polyethylene glycol‐conjugated L‐asparaginase (PEG‐L‐asparaginase) using the human tumor clonogenic assay. Of the 19 myeloma samples evaluated, 63% were inhibited at 0.075 IU/mL, and 74% were inhibited at 0.75 IU/mL. PEG‐L‐asparaginase is a form of Escherichia coli‐derived L‐asparaginase that is bound covalently to polyethylene glycol. Compared with the native form, it has a longer half‐life and is less likely to cause allergic reactions. METHODS The authors conducted a Phase I–II trial using PEG‐L‐asparaginase as a single agent in patients with recurrent and/or refractory multiple myeloma. RESULTS Twenty‐two patients received a median of two doses of PEG‐L‐asparaginase. In the 17 patients who are evaluable for response, a complete response was observed in one patient after four doses, and stable disease was observed in eight patients. Progression of disease was the reason for termination from study in the remaining eight patients. The median survival was 31.7 months, with four patients who were alive at 72 months after the start of therapy. Grade 3–4 toxicity was noted by the PEG‐L‐asparaginase 2000 mg/m2 level. Severe allergic reactions were noted only at the highest dose level. CONCLUSIONS Current data suggest that the maximal tolerated dose for single agent PEG‐L‐asparaginase in relapse/refractory multiple myeloma patients is 1000 mg/m2 every 4 weeks. We could not identify any correlation between dose, plasma level and response. In this advanced group of patients we noted stable disease and/or reponse in 52% of evaluable patients. PEG‐L‐asparaginase has lower tolerance when used in the standard dosage as a single agent in this group of patients. We therefore recommend further studying of PEG‐L‐asparaginase dose of 1000 mg/m2 on alternate weeks with steroids and/or other immune modulators. Cancer 2003;98:94–9. © 2003 American Cancer Society.